The incidence of cognitive impairment and dementia are expected to rise in upcoming years, as the world population shifts toward aging. Acute psychological stress (lasting days to weeks) can temporarily lower cognitive performance, and there is growing evidence that chronic stress (lasting months to years) can accelerate long-term cognitive decline. Thus, understanding the roles of stress and physiological responses to stress (e.g., inflammation) in cognitive aging is critical. Chronic stress can provoke elevated systemic inflammation and exaggerated inflammatory responses, and systemic inflammation has been linked with long- term cognitive decline. However, the physiological mechanisms linking stress with both short- and long-term cognition are not well understood. In addition, the time-course dynamics and means by which stress results in long-term cognitive decline have not been delineated. We hypothesize that stress-related alterations of both the hypothalamic-pituitary-adrenal (HPA) axis and inflammation mediate connections between psychological stress and cognitive performance; further, we expect that chronic stress dysregulates these same biological processes and that this dysregulation increases the risk for cognitive aging. In the proposed research, 320 racially diverse adults, ages 25 to 65, will complete eight biannual bursts of 14 daily assessments to measure daily stress, affect, rumination, and cognitive function. Blood will be collected at the end of each burst, and saliva during each burst, from which we will assess measures of inflammatory state, inflammatory function, and changes in the cortisol awakening response (CAR). We will determine how alterations in stress and these physiological systems relate to changes in cognitive function, as well as how longer-term changes in inflammatory profiles account for cognitive decline. We will examine the extent to which demographic factors (e.g., race, SES, gender, age) moderate these mediation effects. We will also determine the degree to which individuals exhibit heightened rumination and/or emotion across time, and how these factors may extend stress responses, moderate inflammation, and accelerate long-term changes in cognition. This research will be conducted by an interdisciplinary team of scientists who specialize in stress and health, aging and cognition, psychology and emotion, behavior, immunology, and endocrinology. Data from this project will improve understanding of the physiological mechanisms by which stress increases risk of cognitive decline; it will also provide better understanding of the connections between stress, endocrine factors, inflammation, and cognition within a broad psychosocial context over time. In doing so, this project is expected to elucidate novel approaches for intervention by identifying modifiable risk factors for cognitive aging. Because cognitive aging may begin long before old age, understanding its antecedents requires identifying and tracking issues that manifest in early adulthood to midlife. Both stress and inflammation are viable intervention targets, and relate to a broad range of aging-related physical, psychological, and cognitive health outcomes. PUBLIC HEALTH RELEVANCE: With an aging world-wide population, the identification of early diagnostic indices of dementia represents a critical challenge to controlling health care costs and improving quality of life. The goals of this project are to improve understanding of the physiological mechanisms and time-course by which stress in early to mid- adulthood increases risk of cognitive decline, and to better determine the relationships between stress, endocrine factors, inflammation, and cognitive change. As stress and inflammation are both modifiable targets for intervention, this work may also elucidate novel therapeutic approaches to reduce or delay cognitive aging.